1. Field of the Invention
This invention relates to use of a combination of interleukin-2 and an immunotoxin directed against tumor cells in the therapeutic or prophylactic antitumor treatment of mammals using simultaneous or alternate administration of these components.
2. Background Art
Interleukin-2 (IL-2), a lymphokine produced by normal peripheral blood lymphocytes that induces proliferation of antigen or mitogen stimulated T cells after exposure to plant lectins, antigens, or other stimuli, was first described by Morgan, D. A., et al., Science (1976), 193:1007-1008. Then called T cell growth factor because of its ability to induce proliferation of stimulated T lymphocytes, now interleukin-2 is recognized as modulating a variety of functions of immune system cells in vitro and in vivo.
IL-2 was initially made by cultivating human peripheral blood lymphocytes (PBL) or other IL-2-producing cell lines. See, for example, U.S. Pat. No. 4,401,756 Recombinant DNA technology has provided an alternative to PBLs and cell lines for producing IL-2. Taniguchi, T. et al., Nature (1983), 302:305-310 and Devos, R., Nucleic Acids Research (1983), 11:4307-4323 have reported cloning the human IL-2 gene and expressing it in microorganisms.
U.S. Pat. No. 4,518,584 describes and claims muteins of IL-2 in which the cysteine normally occurring at position 125 of the wild-type or native molecule has been replaced with a neutral amino acid, such as serine or alanine Copending U.S. application Ser. No. 810,656 filed Dec. 17, 1985 discloses and claims an oxidation-resistant mutein such as IL-2 which is biologically active wherein a methionine residue of the parental protein which is susceptible to chloramine T or peroxide oxidation is replaced with a conservative amino acid such as alanine. The above IL-2 muteins possess the biological activity of native IL-2. U.S. Pat. Nos. 4,530,787 and 4,569,790 disclose and claim methods for purifying recombinant native IL-2 and muteins thereof, as well as the purified form of IL-2.
U.S. Pat. No. 4,604,377 issued Aug. 5, 1986 discloses an IL-2 composition suitable for reconstituting in a pharmaceutically acceptable aqueous vehicle composed of oxidized microbially produced recombinant IL-2. The IL-2 is noted as useful in combination with cytotoxic chemotherapy or irradiation or surgery in the treatment of malignant or pre-malignant diseases in a direct therapeutic or adjuvant setting or in combination with other immune-modulating drugs, lymphokines (e.g., IL-1, IL-3, CSF-1 and IFNs), or naturally occurring or inducible anti-cellular toxins.
Rosenberg and his coworkers have shown that systemic administration of recombinant IL-2 in high doses causes regression of established metastatic cancers in mice (Rosenberg et al., J. Exp. Med. (1985) 161:1169-1188); and, in conjunction with lymphokine-activated killer cells (Rosenberg, S. et al., New Eng. J. Med. (1985), 313:1485-1492), and tumor-infiltrating lymphocytes (Rosenberg et al., Science (1986) 233:1318-1321), in humans.
Since the mid-1970s, there have been numerous reports of murine monoclonal antibodies that interact with human breast cancer associated antigens. In these reported studies, mice were immunized and boosted with human milk fat globule proteins, breast cancer cell lines or breast cancer membrane extracts. Immune splenocytes were fused with mouse myeloma cells and hybridomas were selected based on some specificity of the culture supernatant for breast or breast cancer antigens. Taylor-Papadimitriou, J. et al., Int. J. Cancer (1981) 28:17-21; Yuan, D., et al., JNCI (1982) 68:719-728; Ciocca, D. R. et al., Cancer Res. (1982) 42:4256-4258.
More recently, investigators at Cetus Corporation have discovered murine monoclonal antibodies that bind selectively to human breast cancer cells, are IgGs or IgMs, and, when conjugated to ricin A chain to form an immunotoxin, exhibit a tissue culture inhibitory dose which results in 50% of control (untreated) protein synthesis (TCID 50%) at immunotoxin concentrations of less than about 10 nM against at least one of MCF-7, CAMA-1, SKBR-3, or BT-20 cells. These antibodies are described more fully in EPC Patent Publication No. 153,114 published Aug. 28, 1985, the disclosure of which is incorporated herein by reference.
In addition, researchers at Cetus Corporation have discovered murine monoclonal antibodies which do not bind to blood cells, have a breast tumor binding range of at least 0.25 (i.e., they bind to at least 25% of breast tumors tested) or have a breast cancer cell line binding range of greater than or equal to 0.25, have a normal tissue reactivity as defined below for human breast and/or ovarian cells equal to or less than 0.09, are IgGs or IgMs, and, when conjugated to an imaging moiety, produce a signal sufficient to image breast cancer tumors. These antibodies include most of those described above and are described more fully in European Pat. Pub. No. 220,858 published May 6, 1987, the disclosure of which is incorporated herein by reference.
Immunotoxins, which are comprised of an antibody conjugated to a toxin, have been used for therapy of various cancers to which the antibody is specific. Certain immunotoxin molecules may be too large to reach the tumor cells efficiently due to poor diffusion out of capillaries.
Combination chemotherapy using two or more anti-cancer drugs to treat malignant tumors in humans is currently in use in research and in the clinic. The anti-cancer drugs may be antimetabolites, alkylating agents, antibiotics, general poisons, etc. Combinations of drugs are administered in an attempt to obtain a synergistic cytotoxic effect on most cancers, e.g., carcinomas, melanomas, lymphomas and sarcomas, and to reduce or eliminate emergence of drug-resistant cells and to reduce side effects of each drug.
Dr. Rosenstein et al., J. Immunol. (1986) 137:1735-1742 disclosed that IL-2 increases the vascular permeability and rate of serum albumin diffusion into organs. Lotze et al., J. Immunol. (1985) 135:2865 disclosed that reversible fluid retention problems result from IL-2 administration.
To applicants' knowledge no one has administered immunotoxin and IL-2 to decrease or eliminate tumor burden